The present invention relates to reactors for performing multiple parallel chemical reactions under pressure and more particularly, to a high pressure chemistry reactor in which the flow of fluid to rows of reaction vessels can be independently controlled by valves interposed between the portions of a two-part manifold fed through a five-way fluid input valve. The reactor includes an explosion proof transparent shield which can be flooded with inert gas.
Drug development in the pharmaceutical industry has changed dramatically due to combinatorial chemistry techniques and automated high-throughput screening. Chemistry laboratories are in need of automated equipment that is capable of screening larger numbers of drug candidates quickly and efficiently. Hence, increasingly sophisticated reactor systems for performing multiple parallel chemistry reactions are being developed.
Such sophisticated equipment is needed for drug screening through the use of catalysts, solvents, reagents and the like, as well as testing for optimal reaction conditions. For example, the efficient screening of catalysts and certain solvents for hydrogenation reactions requires automated equipment capable of maintaining a high pressure environment in the vessels in which the reactions take place.
At one time, such screening was performed in a single pressurized vessel situated on a shaker platform. Only one catalyst or solvent at a time could be tested. To increase throughput in such pressurized catalyst and solvent screening, multiple vessel pressurized reactor systems have been developed. One such system is available from Argonaut Technologies, 887 Industrial Boulevard, San Carlos, Calif. 94070, under the tradename ENDEAVOR. The Argonaut apparatus consists of eight metal jackets or tubes situated in a line. A 15 ml. disposable glass vessel is received in each jacket. The reactions take place within the glass vessels. Each vessel has a separate gas input and is independently temperature and pressure controlled. The metal jackets serve as a safety feature to contain the explosion of an over-pressurized vessel.
While the Argonaut reactor is capable of running eight reactions at one time, the apparatus is quite complex and expensive as separate input, control and monitoring elements are required for each vessel. Thus, set up and run time is long. Moreover, because the reaction vessels are situated within metal tubes, the reactions cannot be observed.
Another example of a multi-vessel pressure reactor which avoids some of the problems of the Argonaut individual vessel gas input and pressure control is available from SmithKline Beecham Pharmaceuticals. That system is described in the paper entitled xe2x80x9cAutomated Catalyst Screening: An Important Tool To Speed-Up the Chemical Process Development In the Pharmaceutical Industryxe2x80x9d by Hiebl et al. given Nov. 18-19, 1999 in Philadelphia, Pa. at the Combinatorial Catalysis and Catalyst Organization ""99.
The Smithkline Beecham pressure reactor consists of a hollow aluminum cylinder with a stainless steel top plate which holds seven individual steel tubes. The pressure reactions are carried out in standard glass vials situated within the steel holding tubes. The aluminum block fits onto a standard Parr shaker. Accordingly, it increases the capacity of a standard Parr shaker by a factor of seven.
Although an individual gas supply is provided for each vessel, all of the vessels are maintained at the same pressure because they are fed from a common feedpipe. Reactions can be carried out at elevated temperatures by pumping a heated liquid through the aluminum block. The reactor can be used in a standard automated synthesis work station and in combination with on-line HPLC analysis equipment.
Another commercially available multiple vessel pressure reactor system in which the pressure in all reactor vessels is controlled simultaneously from a common source is available from Charybdis Technologies, Inc. of 5925 Priestly Drive, Carlsbad, Calif. 92008. Called the Calypso Multi-Temp Reaction Block System, it is constructed of all-glass reaction wells assembled within a PTFE Teflon(copyright) shell, which is resistant to corrosive reagents and organic solvents. The internal cavity of the reactor can be filled with circulating fluid for temperature control. The reactor frame is made of anodized aluminum. It is available in 6, 12, 24, 48 and 96 well formats.
There are the clear advantages of increased throughput and decreased complexity in systems such as those from the SmithKline Beecham and Charybdis Technologies described above, where all reaction vessels are simultaneously pressurized from a common gas input, as compared to the Argonaut system, where each vessel is independently pressurized. However, those systems also have their drawbacks. Cross-contamination of the reaction vessels is a problem because of the common input feed. Loss of all of the reactions will result, should one of the glass vessels rupture. Those systems are also prone to increased flammability, creating a safety hazard. In addition, those reactors lack versatility because it is not possible to pressurize only selected ones of the vessels. In situations where only a limited number of reactions can be performed because of cost considerations, such as due to the use of highly expensive catalysts, this may be a great drawback.
Another disadvantage of those pressure reactors is that fluid introduction and evacuation is complicated, particularly when multiple step purging operations are performed. For example, if vacuum, hydrogen introduction, evacuation and nitrogen introduction steps are required in sequence, or if degassing by several sets of alternating nitrogen introduction and evacuation steps are required, the fluid connections to the reactor must be changed between each step. This is time consuming and labor intensive.
Other problems with commercial reactors of this type relate to the sealing of the glass reaction vessels and the inability to relieve excess pressure build-up which can lead to explosion. Moreover, accurate temperature control is often difficult to achieve.
It is, therefore, a prime object of the present invention to provide a high pressure chemistry reactor with rows of isolated and independently controlled reaction vessels.
It is another object of the present invention to provide a high pressure chemistry reactor in which pressurization of selected rows of reaction vessels is possible.
It is another object of the present invention to provide a high pressure chemistry reactor including a multiple-way input valve capable of connecting the reaction vessels to multiple introduction and evacuation sources without changing the connections.
It is another object of the present invention to provide a high pressure chemistry reactor having improved reaction vessel sealing means.
It is another object of the present invention to provide a tool for use with a high pressure chemistry reactor which facilitates mounting of the reaction vessel sealing means.
It is another object of the present invention to provide a high pressure chemistry reactor with excess pressure relief means.
It is another object of the present invention to provide a high pressure chemistry reactor with increased temperature control accuracy.
It is another object of the present invention to provide a high pressure chemistry reactor including an explosion proof shield surrounding the reaction vessels that is capable of maintaining an inert atmosphere.
In accordance with one aspect of the present invention, apparatus for performing parallel chemical reactions under pressure in a plurality of reaction vessels is provided. The apparatus includes a base with first and second sets of reaction vessel receiving recesses into which reaction vessels are received. At least one of the recess sets has more than one recess. Fluid supply means and fluid manifold means are provided. Means are provided for operably connecting the fluid supply means and the fluid manifold means. The manifold means includes first and second valve means independently operably connecting the fluid supply means to each of the reaction vessels received in each of the first and second sets of reaction vessel receiving recesses, respectively.
The base includes a third set of reaction vessel receiving recesses into which reaction vessels are received. The fluid manifold means has third valve means independently operably connecting the fluid supply means to each of the reaction vessels received in the third set of reaction vessel receiving recesses.
The base includes a fourth set of reaction vessel receiving recesses into which reaction vessels are received. The fluid manifold has fourth valve means independently operably connecting the fluid supply means with each of the reaction vessels received in the fourth set of reaction vessel receiving recesses.
The vessels received in first and second sets of reaction vessel receiving recesses include first and second rows of reaction vessels, respectively. The vessels received in the third set of reaction vessel receiving recesses include a third row of reaction vessels. The reaction vessels received in the fourth set of reaction vessel receiving recesses include a fourth row of reaction vessels.
The fluid supply means includes multiple fluid sources. The connecting means includes a multiple-way fluid input valve. The multiple-way input valve preferably takes the form of a five-way valve.
The manifold means includes means for separately sealing each of the reaction vessels. The sealing means consists of an o-ring and means for affixing the o-ring to the manifold.
The manifold means further comprises a pressure relief valve. This valve provides the important safety feature of relieving excess pressure from the manifold means.
An explosion proof shield may be interposed between the base and the manifold means. It defines an interior space within which the reaction vessels are situated. Means are provided for connecting the interior space of the shield and an inert gas supply.
The manifold means includes a first manifold portion and a second manifold portion. The fluid supply connecting means is connected to the first manifold portion. The first and second valve means include first and second valve bodies which are interposed between the first and second manifold portions.
The first and second valve means have first and second valve stems. The first and second valve stems have different heights so as not to interfere with each other.
Temperature sensing means are provided. One of the reaction vessels received in one of the first and second sets of reaction vessel recesses is adapted to receive the temperature sensing means.
In accordance with another aspect of the present invention, apparatus is provided for performing parallel chemical reactions under pressure in a plurality of reaction vessels. The apparatus includes a base with an array of reaction vessel receiving recesses into which reaction vessels are adapted to be received. Fluid supply means are connected to manifold means. The manifold means includes an input manifold and a distribution manifold. Valve means are interposed between the manifolds. Means operably connect the fluid supply means and the input manifold such that fluid from the supply means passes through the input manifold, the valve means and the distribution manifold, to the reaction vessels.
The reaction vessels received in the vessel receiving recesses are divided into two sets. The valve means includes first and second valves operably connected to the reaction vessels in the first and the second sets, respectively. The distribution manifold includes first and second independent distribution channels. The vessels in the first set are connected to the first distribution channel. The vessels in the second set are connected to the second distribution channel.
A multi-way input valve is interposed between the fluid supply means and the input manifold. A pressure relief valve is connected to the input manifold, as well.
In accordance with another aspect of the present invention, a tool is provided for use in combination with apparatus for performing parallel chemical reactions under pressure in first and second reaction vessels. The apparatus includes fluid supply means and fluid distribution means operably connecting the fluid supply means and the first and second reaction vessels. The fluid distribution means includes a surface and a fluid channel having an internally threaded portion proximate to the surface. A nozzle with an externally threaded hollow cylindrical portion is adapted to be rotatably received within the channel portion. The nozzle also has a hollow head portion with a shoulder. An o-ring is received around the cylindrical portion, between the surface and the shoulder, when the threaded nozzle portion is received within the channel portion. The tool has a rotatable handle and means, attached to the handle, for engaging the nozzle head until the nozzle is rotated to a position wherein the shoulder is spaced from the surface a predetermined distance, such that the o-ring is compressed to the desired degree.
The nozzle head has a surface with a groove. The head engaging means is a height regulator. It includes grooved means for engaging the grooved nozzle head surface until the shoulder is the predetermined distance from the surface. The grooved head surface is a conical section tapered inwardly from the shoulder towards the end of the head. The head engaging means includes a hollow cylindrical part adapted to receive the head.
The handle preferably has a hexagonally shaped stem. The head engaging means includes a hexagonally shaped opening adapted to receive the stem.
The head engaging means is a height regulator.
The head engaging means includes a hollow, generally cylindrical part adapted to receive the head. That part includes an internally grooved surface.